|Year : 2019 | Volume
| Issue : 1 | Page : 13-22
Tuberculous meningitis: A narrative review
Pulikottil Wilson Vinny1, Venugopalan Y Vishnu2
1 Department of Neurology, INHS Asvini, Mumbai, Maharashtra, India
2 Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||20-Apr-2019|
|Date of Acceptance||23-Apr-2019|
|Date of Web Publication||19-Jun-2019|
Venugopalan Y Vishnu
Department of Neurology, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
Tuberculous meningitis (TBM) is a medical emergency. It is the most devastating manifestation of tuberculosis (TB). The outcome depends on early diagnosis and appropriate treatment. Empirical antituberculous therapy should be started if clinical suspicion is high. All patients should be tested for HIV. The choice of antituberculous drugs is extrapolated from pulmonary TB regimen, and many drugs have poor cerebrospinal fluid penetration. More evidence is required to guide on drug therapy in TBM. Steroids should be used as adjunctive therapy and response may be modulated by host genotype. Active monitoring should be done for complications such as hydrocephalus, hyponatremia, and stroke.
Keywords: Antituberculous therapy, guideline, tuberculoma, tuberculosis, tuberculous meningitis
|How to cite this article:|
Vinny PW, Vishnu VY. Tuberculous meningitis: A narrative review. J Curr Res Sci Med 2019;5:13-22
| Introduction|| |
Tuberculosis (TB) is a major global health problem and remains a major public health issue in India. Mycobacterium TB can practically affect any part of the body but when the brain is involved, the consequences are devastating. Tuberculous meningitis (TBM) is the most devastating and disabling form with around 1 lakh new cases appearing every year around the world. The incidence and prevalence of TBM varies around the world depending on location, age group, and prevalence of HIV. In 2017, eight countries (India, China, Indonesia, Philippines, Pakistan, Nigeria, Bangladesh, and South Africa) accounted for two-thirds of all TB cases. The major risk factors causing the TB epidemic are urbanization, crowding, poverty, malnutrition, injection drug use, chronic use of steroids, chronic renal failure, incarceration, HIV, diabetes, and alcoholism. The major gaps in diagnosis and treatment are caused by delayed presentation, reliance on complementary or traditional medicine, inability to perform or refusal of lumbar puncture, lack of laboratory facilities, and unavailability or unaffordability of antibiotics. Indian national guidelines for extrapulmonary TB estimates that TBM constitutes 1% of all TB cases. The diagnosis of TBM is not easy and hence mostly underreported. The neonatal bacillus Calmette–Guérin (BCG) vaccine might be 73% effective in preventing TBM. The mortality rate of TBM remains very high. A Cochrane review reported 41% and 31% of mortality in TBM with or without steroids. Even with antiretroviral therapy (ART), the mortality of TBM in HIV coinfection is around 40%., The mortality is near 100% in drug-resistant TBM with HIV-1 coinfection.
| Pathogenesis|| |
Mycobacterium TB is an airborne infection with lung as thefirst portal of entry. The infection initially replicates in the lungs and then moves to the lymph nodes. The dissemination of TB bacilli via blood accounts for the extrapulmonary TB, including TBM. The bacilli settle and form a localized granuloma called rich focus in the meninges or parameningeal areas. The rupture of rich focus causes the bacilli to spill into subarachnoid space, eventually involving the brain parenchyma and blood vessels. The brain parenchymal involvement can be tuberculoma or abscess. The inflammation of the meninges leads to basal exudates in the base of the brain and causes inflammation of vessels (vasculitis) that may result in vascular occlusion causing strokes. The most commonly involved vessels are perforating branches of the middle cerebral artery leading to infarcts in the basal ganglia and internal capsule. The ischemia may be further worsened by the raised intracranial pressure (ICP) and hydrocephalus due to obstruction of cerebrospinal fluid (CSF) flow by basal exudates.
In children and HIV-1 coinfection, TBM can occur as part of initial disseminated infection. In HIV-TB coinfection, there is higher frequency of extrapulmonary TB, especially TBM accompanied by occult meningeal disease and higher blood culture positivity (40%) in HIV-1 co-infection., HIV-1 coinfected individuals are more likely to experience TBM-associated Immune Reconstitution Inflammatory Syndrome (IRIS) since initiation of antiretroviral therapy might unmask the occult meningeal disease.
TBM pathogenesis involves both bacterial replication in brain as well as dysregulated host immune response including reactive oxygen species.Mycobacterium TB bacilli are taken up by microglia once they cross the blood–brain barrier. Multiplication of bacilli inside the microglia leads to cytokine and chemokine production. Many patients manifest pituitary dysfunction which is significant considering that steroids are used in treatment of TBM. interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-1β, and matrix metalloproteinases are the cytokines found to be related to immunity and survival of TBM.
Genetic polymorphisms in various host response genes can modulate the immune response in TBM. A single-nucleotide polymorphism in the leukotriene A4 hydrolase (LTA4H) promoter can affect the balance between pro-inflammatory leukotriene B4 and immunosuppressive lipoxin A4. LTA4H polymorphism is associated with inflammatory cell recruitment, survival of TBM patients, and response to anti-inflammatory treatment.
| Clinical Features|| |
The clinical features of TBM are nonspecific. Important differential diagnoses include partially treated pyogenic meningitis and cryptococcal meningitis. The common symptoms and signs of TBM are fever, headache, vomiting, neck stiffness, fatigue, loss of weight, loss of appetite, altered sensorium, and focal deficits (cranial nerve palsies, vision loss, hemiparesis, and paraparesis). The onset is usually insidious with a prodromal stage lasting for days to weeks (fatigue, loss of weight/appetite, and night sweats) followed by features of meningitis (fever, headache, and neck stiffness). If untreated, the patient can present with various complications such as altered sensorium, cranial nerve palsies, hemiparesis, or coma. TBM is a medical emergency. Treatment before the onset of coma is the greatest benefit a physician can give a patient with TBM. In endemic region like India, the pretest probability of TBM is high, and empirical treatment should be considered in a patient suspected to have TBM.
The clinical features also depend on the host immune response. In very young children (<1 year of age) and HIV-1 coinfection, extrapulmonary dissemination and TBM are common. Moreover, they can have an abrupt and rapidly progressive presentation to coma with high morbidity and mortality. The Medical Research Council (MRC) disease severity grade strongly predicts outcome in TBM [Table 1]., The other important risk factors for mortality include HIV-1 coinfection, extremes of age, and drug-resistant TB.
Several clinical scoring systems have been studied to find the diagnostic predictors of TBM depending on age group, setting, and HIV status [Table 2]. Few have been externally validated. However, not all externally validated scores have fared well in terms of sensitivity and specificity. Thwaites score, which was validated in multiple countries, did not fare well in HIV coinfected Malawi population (sensitivity 78% and specificity of 43%) where most false-positive cases turned out to be cryptococcal meningitis.,
|Table 2: Various clinical scores for diagnostic predictors of tuberculous meningitis|
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A consensus case definition for TBM was published mainly for research purpose and was not very useful when employed as a clinical diagnostic tool.,
| Imaging|| |
Computed tomography (CT) and magnetic resonance imaging (MRI) are the commonly used modalities for imaging. MRI has better resolution in detecting tuberculomas and infarct. The common brain imaging features in TBM are basal exudates, tuberculomas, and hydrocephalus [Figure 1]. Ring-enhancing lesions are common presentation of tuberculomas and tubercular abscess. The common differentials are neurocysticercosis, bacterial abscess, fungal abscess, metastasis, gliomas, lymphomas, and toxoplasmosis [Table 3], [Table 4], [Table 5].
|Figure 1: Magneatic resonance imaging brain T1 contrast imaging showing basal exudates encasing the vessels|
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|Table 5: Imaging differentiation between neurocysticercosis and tuberculoma|
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| Diagnosis|| |
The detection of TB bacilli by Ziehl–Neelsen staining has been the main method of early diagnosis of TB. However, its sensitivity in TBM is only 10%–20%. The sensitivity of CSF microscopy can be augmented by taking large volume CSF (10 ml), centrifuging at 3000 RPM, and examining for 30 min by experienced microbiologist. The culture takes minimum 10 days in liquid media and 8 weeks in solid media. Hence, cultures in TBM rarely help in the decision-making process regarding treatment.
Many nucleic acid amplification tests have been developed, but few are well validated., GeneXpert is a real-time polymerase chain reaction-based assay for detection of Mycobacterium tuberculosis in clinical specimens and also detect rifampicin resistance-associated mutations. The assay is approximately 60% sensitive and nearly 100% specific. The test should be used to “rule-in” and not “rule-out” the diagnosis of TBM.,, GeneXpert Ultra is the second-generation assay works on detection and amplification of a multicopy gene target and is reported by the WHO to have 95% sensitivity.
Blood and CSF IFN-γ release assays have a sensitivity of 78% and 77%, respectively, with specificity of 61% and 88%, respectively. This limits its utility in clinical practice.
Similarly, CSF adenosine deaminase (ADA) value of 1–4 U/l have a sensitivity of >93% and specificity of <80%, while CSF ADA >8 U/l have sensitivity of >96% and specificity of <59%. These cutoff values, however, could not consistently differentiate between TBM and bacterial meningitis.,
The features detected on imaging may have good specificity, but sensitivity remains low. A combination of basal exudates, hydrocephalus, and infarcts on CT brain have high specificity (95%–100%), but these may be absent in early stage of the disease, reducing its sensitivity to around 40%. MRI might pick up more tuberculomas and infarcts. More than 50% of TBM have concomitant spinal cord involvement, and around 50% have chest X-ray abnormalities. Miliary mottling of chest X-ray suggests dissemination. CT or positron emission tomography-CT of chest, abdomen, and pelvis can detect TB in other organs that may offer easier site for biopsy.
The main limitation of imaging as a diagnostic modality is that 30% of cases at MRC-Grade I have normal CT scan and 15% have normal MRI brain. Age and HIV-coinfection significantly affect the imaging appearance. Children have more hydrocephalus. HIV-coinfected TBM patients have less basal exudates, especially with low CD4 counts.,
| Management|| |
The management of TBM consists of three strategies:
- Killing the TB bacilli with antitubercular treatment (ATT)
- Manage the host immune response
- Supportive care and manage the complications.
The greatest predictor of survival from TBM is the initiation of ATT before the onset of coma. We still do not have high-quality evidence regarding the ideal combination, dosage, frequency of administration, or duration of treatment in TBM. The treatment strategy is based on the pulmonary TB (PTB) management regimens. The characteristics of antituberculous agents are described in [Table 6].
In central nervous system (CNS) TB, the major concerns are poor CSF penetration of rifampicin and ethambutol. Most of the guidelines and recommendations do not consider the poor CSF penetration of these drugs. Whether a higher dose of rifampicin should be used in TBM is not clear. An open-label randomized controlled trial conducted in Indonesia with 60 TBM patients showed that use of 600 mg of rifampicin intravenously could halve the mortality compared to 450 mg oral dosing. However, a larger trial with 817 patients in Vietnam which tested higher dose of rifampicin (15 mg/kg vs. 10 mg/kg orally) and levofloxacin (first 2 months) did not show any survival benefit. The probable reason for failure may be higher dose requirement of rifampicin. In a dose-ranging trial in PTB, doses up to 35 mg/kg were safe and highest doses (30 and 35 mg/kg) showed highest bactericidal activity.
The choice of the fourth drug remains ambiguous. There are no comparative trials available. Commonly used drugs are ethambutol and streptomycin. Both have low CSF penetration and exhibit adverse events in the form of optic neuropathy and vestibular toxicity respectively. The rationale in drug-sensitive PTB is to prevent isoniazid resistance, as it does not increase bacterial killing or improve outcome. But in TBM, the rationale of the fourth drug is also to increase bacterial killing, and patient survival since the CSF penetration of rifampicin is low. Ethionamide has better CSF penetration (80%–90%). Levofloxacin and moxifloxacin also have better penetration (70%–80%) with high activity against TB bacilli (drug susceptible and drug-resistant). The intensified regimen (levofloxacin as the 5th drug along with ethambutol and high-dose rifampicin) tested in a randomized controlled trial in Vietnam failed to show any survival benefit, though there was increased survival in patients with isoniazid-resistant TB bacilli. Hence, in drug-susceptible TBM, choice of the 4th drug might not influence patient outcome, but in isoniazid resistance, high-dose rifampicin (15 mg/kg) and levofloxacin (as fifth drug) might improve the outcome.
Drug-resistant TBM has very poor outcome with mortality >80%. There is usually delay in detection of drug resistance even with GeneXpert (sensitivity <60%). CSF penetration and efficacy of second-line drugs are not well defined.
The Index TB guidelines recommend 2 months of HRZE and 7 months of HRE [Table 7]. The WHO guidelines recommend 2 months HRZS followed by 10-month continuation phase with HR. The current RNTCP guidelines recommend 2 months or HRZE and 9–12 months of HRE.
|Table 7: Summary of index tuberculosis guidelines regarding tuberculous meningitis|
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There are various issues with these guidelines. There is clinical equipoise regarding the duration of treatment in TBM. Most of what is recommended in the guidelines are expert opinion. The neurologists in general and also those in the Index-TB guideline panel feel that TBM should be treated for minimum for 12–18 months. The Technical Advisory Subcommittee for CNS TB who drafted Index-TB guidelines preferred pyrazinamide instead of ethambutol. Many physicians and neurologists prefer streptomycin instead of ethambutol, especially when TBM threatens vision loss and due to risk of ethambutol-related optic neuropathy. However, both drugs have poor CSF penetration.
Only high-quality randomized controlled trials at a larger scale can answer this question. It is ironic that the streptomycin was thefirst drug in medicine to be tested in a randomized controlled trial, and still half a century later, we still do not have RCTs to guide us regarding treatment of TBM.
| Role of Anti-Inflammatory Therapy|| |
Adjunctive corticosteroids are hypothesized to reduce inflammation in TBM and hence improve patient outcomes. Cochrane Systematic Review and Meta-analysis in 2016 concluded that corticosteroids increase survival in TBM (children and adults) who were HIV-1 negative. In HIV-1 coinfection, the benefit of steroids was uncertain. There was no reduction in long-term disability in any group. In the Vietnam trial, however, there were 98 HIV-1-coinfected TBMs, and in this subgroup, there was no significant effect of steroids on death or combined end-point of death and disability.
Delayed inflammatory reaction which occurs weeks to months after starting ATT is called paradoxical reaction. In HIV-coinfected patients, after starting ART, it is called IRIS. Paradoxical reaction and IRIS may present with fever, worsening headache, seizures, or altered sensorium. When suspected, hydrocephalus, infarcts, or tuberculoma formation should be identified by imaging. The most commonly described paradoxical reaction is tuberculoma. They are commonly treated with high-dose steroids. When there is no response to steroids or clinically patient worsens, other anti-inflammatory therapies may be tried, especially in the setting of tuberculoma at optic chiasma or when optochiasmatic arachnoiditis threatens vision. Thalidomide, infliximab, and IFN-γ have been tried in such scenarios.,,, Modi et al. has reported use of thalidomide (in a dose of 2 mg/kg) for 4–6 months in >50 patients with TBM (who had already received >2 months of ATT and steroids) suffering from various inflammatory complications (such as optochiasmatic arachnoiditis, a paradoxical increase in the size of tuberculomas, an increase in size and number of lesions, and spinal arachnoiditis). The authors have claimed clinical and radiological improvement in >70% of patients.
Genetic polymorphism in some immune response genes can modulate pro-inflammatory and anti-inflammatory host responses. Much focus is on single polymorphism in LTA4H promotor which modulates eicosanoids and thus influencing TNF-α expression., In the Vietnam trial where all participants received steroids, survival benefit was present in TT genotype (hyperinflammatory), and there was harm in CC genotype. But in an Indonesian study, LTA4H genotype did not show any survival benefit in 427 HIV-negative patients with TBM where all received corticosteroids. Hence, the clinical evidence on LTA4H genotype guiding personalized anti-inflammatory treatment is ambiguous as of now.
Index TB recommendation for dosing of steroids in TBM is “In hospital: intravenous dexamethasone 0.4 mg/kg/24 h in 3–4 divided doses may be preferred with a slow switch to oral therapy and taper. Currently, there is insufficient evidence to recommend one formulation/regimen of steroids over any other.”
Other than steroids, the only adjunctive treatment with proven benefit in CNS TB is ART. There is ambiguity in the timing of initiation of ART. The choice is between reducing the risk of other opportunistic infections with early ART versus risk of IRIS. A single trial comparing early versus 2 months delayed initiation of ART in TBM showed no survival difference, but severe adverse events were more in early ART group.
Tuberculomas can present along with TBM or occur independently. The clinical features depend on site and size. They can present with seizures, focal deficit, raised ICP due to hydrocephalus, or mass effect. Tuberculomas can appear a part of paradoxical worsening or IRIS. The main treatment is ATT and duration of treatment is uncertain. The usual practice is to continue treatment till 18 months or till tuberculoma disappears. When there is no response to ATT and steroids, especially in locations such as optochiasmatic region, other anti-inflammatory agents like thalidomide are used.
| Supportive Management|| |
The various complications of TBM (increased ICP, infarct, hydrocephalus, hyponatremia, and seizures) should be detected early and managed appropriately. Raised ICP is managed symptomatically by mannitol or hypertonic saline.,
Hydrocephalus is the most common cause of increased ICP, and 80% have communicating hydrocephalus due to disruption of CSF flow due to basal exudates [Table 8]. Communicating hydrocephalus might be treated with diuretics and serial lumbar punctures., Noncommunicating hydrocephalus is treated with ventriculoperitoneal (VP) shunt or endoscopic third ventriculostomy (ETV). A systematic review of VP shunt in TBM concluded that clinical severity determines the outcome and HIV-1 coinfection had worse prognosis. A trial on 48 patients with TBM and hydrocephalus comparing VP shunt and ETV, showed that ETV had higher risk of early recurrence, but lesser long-term complications than VP shunt. However, it is technically difficult to do ETV in TBM Hydrocephalus in acute stage with inflamed, opaque, and thick third ventricle., The contrary viewpoint is that aqueductal stenosis in early-stage TBM should be managed by ETV and VP shunt should be used for chronic burnt out cases or those with communicating hydrocephalus. Ambiguity in selection of one procedure over other for TBM hydrocephalus continues in the absence of robust evidence.
|Table 8: Modified Vellore Grading Scale for hydrocephalus in tuberculous meningitis and Glasgow Outcome Scale|
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Hyponatremia in TBM could be due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) or cerebral salt wasting syndrome (CSWS), and it is difficult to differentiate between them clinically. SIADH is managed by fluid restriction, while CSW is treated by fluid administration [Table 9].
|Table 9: Features of cerebral salt wasting syndrome and syndrome of inappropriate antidiuretic hormone|
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Recently, a small trial with 36 patients assessed safety and efficacy of fludrocortisone in the treatment of cerebral salt wasting in patients with TBM. It was published as an open-label randomized controlled trial with 0.9% intravenous saline solution with 5–12 g per day of oral salt supplementation, with or without the addition of 0.1–0.4 mg of fludrocortisone per day. Fludrocortisone resulted in early normalization of serum sodium levels but did not affect outcomes in 6 months. The study was plagued by significant discrepancy between the retrospectively registered trial protocol and the published paper. The paper brought out fludrocortisone as a treatment option in CSWS that is worth pursuing in future randomized controlled trials.
Stroke due to TB vasculitis are usually multiple and bilateral involving deep gray matter like caudate/ thalamus as also anterior and genu of internal capsule ("tubercular zone"). There is no proven treatment or prevention of stroke in TBM. Corticosteroids were not found to be effective in preventing brain infarction. Aspirin might prevent stroke in TBM as shown in two small trials.,
| Prevention|| |
Three most effective preventive strategies for TBM are (1) reducing transmission of Mycobacterium TB, (2) BCG vaccination in neonates (reduces the incidence of dissemination including TBM), and (3) ART in people with HIV.
| Drug-Resistant Tuberculous Meningitis|| |
Multidrug-resistant TB is resistant to at least isoniazid and rifampicin. Extensively drug-resistant TB is resistant to isoniazid and rifampicin, as well as any fluoroquinolones and any of the three second-line injectable ATT drugs (amikacin, kanamycin, or capreomycin). Drug resistance could be primary (due to the transmission of drug-resistant strain in someone who was not taking ATT) or acquired (resistance developing in someone who was already taking ATT). The WHO guidelines for the treatment of multidrug-resistant TBM recommend that initially at least five effective drugs should be used comprising a fluoroquinolone and an injectable second-line agent and duration of treatment should be 18–24 months. It is uncertain regarding the clinical decision point of presumptive treatment failure in TBM.
It may not be acceptable to wait more than 3 months to decide on presumptive treatment failure.
| Conclusion|| |
TBM is a medical emergency associated with high morbidity and mortality. Early empirical treatment with ATT should be started if clinical suspicion is high. Ensuring compliance with chosen ATT regimen and supportive therapy cannot be overemphasized. Current ATT regimens are extrapolated from PTB regimens and do not consider poor CNS penetration of drugs such as ethambutol, streptomycin, and rifampicin. Improvement in social indicators of a country, namely, malnutrition, poverty, and low income will play an important role in the prevention and control of TB.
The authors would like to thank Dr. Rajesh Kumar Singh.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]